The endogenous factors contributing to complex disease entities can often be revealed by analyzing strains of mice differing in their susceptibilities. The ideal system should permit us to determine the number, location and function of the genes contributing these complicated disease entities. The principle of the analysis is well-established. One constructs a set of recombinant inbred (RI) strains between progenitors which differ with respect to the traits one wishes to analyze. The RI strains are then characterized for these traits and genetic conclusions drawn. We propose to study the progenitors BALB/c(C) and SJL/J(J) plus a derived family of 13 (BXS)RI strains which we have constructed. Those strains differ in their behavior with respect to susceptibility to a large number of pathogens, tumors, autoimmunity, and ageing. The usefulness of a set of RI strains depends on the number of known loci which have been identified in each one. If the set of markers is large enough a new allele can be mapped with precision by comparisons of its distribution in the strains. Thus far our RI strains have been typed for a number of known markers e.g. H-2, Igh and Lambda1. This aspect is being extended by 1) further typing of known alleles and 2) searching for restriction enzyme site polymorphisms, a new and powerful methodology. A well-characterized (CXJ)RI family will thus enable us to carry out precision mapping of the more complicated phenotypes. This family is being used in a multilaboratory effort to determine where the genes are that control 1) expression of Lambda1 immunoglobulin; 2) NK/NC levels; 3) induction of myelomas by pristane; 4) spontaneous tumor incidence; 5) specific alloresponsiveness; 6) antigen-specific T-cell reactivity which is non-H-2 linked i.e. the locus encoding the T-cell receptors; 7) susceptibility to autoimmune encephalitis, Leishmania, Mycobacteria, Salmonella, Streptococci, Listeria, murine hepatitis virus; 8) ability to mount a DTH response; 9) site specific integration of ecotropic murine leukemia viruses; 10) establishing of tolerance and age-dependent autoimmunity; 11) nonrandom chromosomal rearrangements associated with lymphoid tumors; and 12) the levels of various enzymes in different tissues.